19-Hydroxy-19-methyl-6-oxo-PGF1 amides

ABSTRACT

The present invention provides novel 19-hydroxy-19-methyl-6-oxo-PGF 1  amides which are useful for pharmacological purposes, e.g., anti-asthmatic indications.

CROSS REFERENCE TO RELATED APPLICATION

The present invention is a divisional application of United States Ser.No. 054,720, filed July 5, 1979, now U.S. Pat. No. 4,225,507.

BACKGROUND OF THE INVENTION

The present invention provides novel prostacyclin analogs. Particularly,the present invention relates to prostacyclin analogs substituted at theC-19 position by hydroxy.

Particularly, the present invention relates to19-hydroxy-19-methyl-6-oxo-PGF₁ amides. The novel prostacyclin analogsare useful for pharmacological purposes, e.g., as anti-asthmatic agents.The preparation and use of these compounds is incorporated here byreference from U.S. Pat. No. 4,225,507.

PRIOR ART

For background on prostacyclin, see for example R. A. Johnson, et al.,Prostaglandins 12, 915-928 (1976) and R. A. Johnson, et al., J. Am.Chem. Soc. 100, 7690-7704 (1978), and, as to pharmacological activity,the references cited therein. For analogs of prostacyclin, see, forexample, J. Fried, et al., Proc. Natl. Acad. Sci. U.S.A. 74, 2199-2203,K. C. Nicolaou, et al., J.C.S. Chem. Comm. 1977, 331-332, N. A. Nelson,J. Am. Chem. Soc. 99, 7362-7363 (1977), and K. Kojima, et al., Tetra.Letters, 1978, (1977), and K. Kojima, et al., Tetra. Letters, 1978,3743-3746. Regarding the nomenclature for analogs of PGI₂, see R. A.Johnson, et al., Prostaglandins 15, 737-740 (1978).

SUMMARY OF THE INVENTION

The present invention particularly provides

a prostacyclin-type compound of the formula ##STR1## wherein D is--(CH₂)₂ --CO--CH₂ --L₂ -- or --CH₂ --CO--CH₂ --L₃ --

wherein L₂ is

(1) --(CH₂)_(j), wherein J is one to 4, inclusive,

(2) --(CH₂).sbsb.q--CF₂ --, wherein q is one, 2, or 3, or

(3) --CH═CH--,

wherein L₃ is

(1) --(CH₂).sbsb.n--, wherein n is one to 5, inclusive,

(2) --(CH₂).sbsb.p--CF₂ --, wherein p is 2, 3, or 4, or

(3) --CH₂ --CH═CH--;

wherein Q is oxo, α-H:β-H, α-OH:β-R₄, or α-R₄ :β-OH,

wherein R₄ is hydrogen or alkyl of one to 4 carbon atoms, inclusive,

wherein R₂ is hydrogen, hydroxyl, or hydroxymethyl;

wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms,inclusive, or fluoro, being the same or different, with the proviso thatone of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro;

wherein R₇ and R₈ are hydrogen, alkyl of one to 12 carbon atoms,inclusive, benzyl, or phenyl, being the same or different; wherein X is

(1) trans--CH═CH--,

(2) cis--CH═CH--,

(3) --C.tbd.C--, or

(4) --CH₂ CH₂ --.

I claim:
 1. A prostacyclin-type compound of the formula ##STR2## whereinD is --(CH₂)₂ --CO--CH₂ --L₂ -- or --CH₂ --CO--CH₂ --L₃ --wherein L₂ is(1) --(CH₂).sbsb.j, wherein j is one to 4, inclusive, (2)--(CH₂).sbsb.q--CF₂ --, wherein q is one, 2, or 3, or (3)--CH═CH--,wherein L₃ is (1) --(CH₂).sbsb.n--, wherein n is one to 5,inclusive, (2) --(CH₂).sbsb.p--CF₂ --, wherein p is 2, 3, or 4, or (3)--CH₂ --CH═CH--;wherein Q is oxo, α-H:β-H, α-OH:β-R₄, or α-R₄ :β-OH,wherein R₄ is hydrogen or alkyl of one to 4 carbon atoms,inclusive,wherein R₂ is hydrogen, hydroxyl, or hydroxymethyl; wherein R₅and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, orfluoro, being the same or different, with the proviso that one of R₅ andR₆ is fluoro only when the other is hydrogen or fluoro; wherein R₇ andR₈ are hydrogen, alkyl of one to 12 carbon atoms, inclusive, benzyl, orphenyl, being the same or different; wherein X is (1) trans--CH═CH--,(2) cis--CH═CH--, (3) --C.tbd.C--, or (4) --CH₂ CH₂ --.